The super elongation complex drives transcriptional addiction in MYCN-amplified neuroblastoma.
The super elongation complex drives transcriptional addiction in MYCN-amplified neuroblastoma.
复制标题
DOI：
10.1126/sciadv.adf0005
复制
发表时间：
2023-03-29
期刊：
影响因子：
13.6
通讯作者：
Qing, Guoliang
中科院分区：
文献类型：
--
作者：
Wang, Donghai;Yin, Zhinang;Wang, Honghong;Wang, Liyuan;Li, Tianyu;Xiao, Ruijing;Xie, Ting;Han, Ruyi;Dong, Rui;Liu, Hudan;Liang, Kaiwei;Qing, Guoliang
神经母细胞瘤中MYCN扩增导致MYCN癌蛋白的异常表达，其结合促进转录扩增的活性基因。然而，MYCN如何协调转录延伸以满足生产性转录扩增，以及哪些延伸机制代表MYCN驱动的脆弱性仍有待确定。我们对转录延伸因子进行了靶向筛选，并将超延伸复合物（SEC）鉴定为MYCN扩增的神经母细胞瘤的独特脆弱性。MYCN直接结合EAF 1并募集SEC以增强进行性转录延伸。EAF 1或AFF 1/AFF 4（SEC的另一个核心亚基）的缺失导致MYCN扩增的神经母细胞瘤细胞的转录延伸和elevently选择性凋亡的整体减少。联合筛选显示SEC抑制协同增强FDA批准的BCL-2拮抗剂ABT-199的治疗功效，部分原因是在MYCN扩增的神经母细胞瘤细胞和患者来源的异种移植物中抑制了MCL 1表达。这些发现确定了MYCN-SEC调节轴的破坏作为神经母细胞瘤的有希望的治疗策略。MYCN通过EAF 1募集SEC以促进进行性转录延伸。
MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet, how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL-2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma. MYCN recruits SEC through EAF1 to promote processive transcription elongation.
登录
查看更多内容
影响因子：
64.5
作者：
Liang K;Smith ER;Aoi Y;Stoltz KL;Katagi H;Woodfin AR;Rendleman EJ;Marshall SA;Murray DC;Wang L;Ozark PA;Mishra RK;Hashizume R;Schiltz GE;Shilatifard A
通讯作者：
Shilatifard A
影响因子：
17.1
作者：
Carter DR;Murray J;Cheung BB;Gamble L;Koach J;Tsang J;Sutton S;Kalla H;Syed S;Gifford AJ;Issaeva N;Biktasova A;Atmadibrata B;Sun Y;Sokolowski N;Ling D;Kim PY;Webber H;Clark A;Ruhle M;Liu B;Oberthuer A;Fischer M;Byrne J;Saletta F;Thwe le M;Purmal A;Haderski G;Burkhart C;Speleman F;De Preter K;Beckers A;Ziegler DS;Liu T;Gurova KV;Gudkov AV;Norris MD;Haber M;Marshall GM
通讯作者：
Marshall GM
影响因子：
14.9
作者：
Perez-Riverol Y;Bai J;Bandla C;García-Seisdedos D;Hewapathirana S;Kamatchinathan S;Kundu DJ;Prakash A;Frericks-Zipper A;Eisenacher M;Walzer M;Wang S;Brazma A;Vizcaíno JA
通讯作者：
Vizcaíno JA
ENL 启动超延伸复合物 (SEC) 的多价相分离来控制快速转录激活
影响因子：
13.6
作者：
Guo, Chenghao;Che, Zhuanzhuan;Lin, Chengqi
通讯作者：
Lin, Chengqi
影响因子：
16
作者：
Baluapuri, Apoorva;Hofstetter, Julia;Wolf, Elmar
通讯作者：
Wolf, Elmar